Blood Oxygen Level Dependent (BOLD) functional magnetic resonance imaging (fMRI) is used ubiquitously to map the human brain, both in health and disease. Instead of directly measuring neuronal activity, BOLD fMRI detects perfusion-dependent signals that are coupled to neuronal activity. The accurate interpretation of BOLD fMRI signals is compromised by an incomplete understanding of the precise relationship between electrophysiological activity, functional anatomy, and function perfusion. The overall goal of this research program is to examine the precise relationship between electrophysiology, connectivity, and BOLD fMRI signals across tasks, cortices, and disease states. Candidate: Given his solid neuroscience training, thorough general and sub-specialty (functional) neurosurgical training, and quality research experiences, Dr. Nader Pouratian has already published extensively in the field of human brain mapping. This career development and research proposal represents a natural extension of his previous work which employed multimodality imaging to characterize the etiology, limitations, and capacities of perfusion-dependent brain mapping signals in humans using fMRI, optical imaging, and electrocortical stimulation mapping (ESM). In an environment rich in imaging expertise, the immediate goals are to develop and ensure the breadth and the depth to function as THE imaging expert on a grant proposal. Specific career development goals of this proposal are (1) to gain expertise in additional brain mapping methodologies (electrocorticography and diffusion tractography) in order to become a more comprehensive and well-rounded brain mapping expert (2) to gain facility with and proficiency in complex statistics and signal and image analyses (3) to augment the candidate's fund of knowledge in advanced systems neuroscience (4) to obtain advanced training in the scientific method and (5) to ensure continued training in the ethical conduct of research. These goals will be accomplished by means of hands-on laboratory experience, mentorship and guidance of world-renowned leaders (Drs. Arthur Toga, Susan Bookheimer, Itzhak Fried, Robert Knight, and Jeffrey Ojemann) both within and outside of UCLA and dedicated coursework and seminars. The candidate's long-term research focus is devoted to the precise and accurate mapping and interpretation of human brain function that can be used both to advance systems-level characterization of motor and language systems and to develop restorative neurosurgical interventions. Environment: Research and career development activity will primarily be conducted at UCLA, which ranks among the nations top ten research universities and has a record of excellence which is attributable to a strong network of resources, research, education and collaborative opportunities. The state-of-the-art image acquisition and analysis facilities including the UCLA Laboratory of Neuro Imaging (LONI) and the Ahmanson-Lovelace Brain Mapping Center provide an unparalleled and enriched environment for career development that is particularly suited for career enhancement in the field of neuroimaging and clinical neuroscience. Research within LONI is focused on improving the understanding of the brain in health and disease by using computational approaches for the comprehensive mapping of brain structure and function. UCLA's institutional environment promises to promote the candidate to a new level of academic excellence. Research: The overriding hypothesis is that BOLD fMRI signal characteristics are determined by a complex combination of integrated electrophysiological activity (i.e., multiple field potential bands) that vary across cortices and tasks and are modulated by system capacities, limitations, and buffers. We hypothesize that functionally significant signals can be differentiated from non-specific activations based on unique response profiles and patterns of anatomic connectivity. In Specific Aim 1, we will specifically investigate the electrophysiologic basis of the spatial extent of BOLD fMRI signals across cortices, tasks, and task complexity by comparing BOLD and ECoG signals within subjects using finely-tuned motor and language tasks and multivariate analyses. We hypothesize that BOLD spatial extent is electrophysiologically-determined but dependent upon the extent of low-frequency field potential activity rather than high-frequency activity and that a neurovascular buffer exists such that not all electrophysiological changes instigate changes in perfusion. In Specific Aim 2, we critically analyze the electrophysiologic determinants of BOLD signal intensities, with detailed BOLD-ECoG comparisons designed to determine the variability of these relationships across cortices, tasks, and disease states, whether electrophysiologic and BOLD signals respect similar rules of additivity and adaptation, and how BOLD ceiling responses relate to electrophysiology. In Specific Aim 3, we address the hypothesis that functionally relevant brain mapping signals can be differentiated based on distinctive connectivity based biomarkers. Using multimodality comparisons, we will critically scrutinize the relationship between BOLD signals, ESM, DTI tractography, and BOLD and ECoG signal coherence to elucidate the role of connectivity in delineating significant BOLD fMRI activations. Summary: This career development grant combines key elements from the candidate's background and unique and outstanding institutional resources with the development of the skills required to achieve the goal of becoming an independent investigator with a locally unique Neurosurgical Brain Mapping and Restoration Lab at UCLA. PUBLIC HEALTH RELEVANCE: Blood Oxygenation Level Dependent (BOLD) functional magnetic resonance imaging (fMRI) is used ubiquitously to study brain function and organization, both clinically and for research in health and disease. Yet, to date, there is an incomplete understanding of what these signals represent, how they relate to underlying neuronal activity in space and magnitude, and ultimately how representative these signals are of brain function and organization. By combing BOLD fMRI studies with electrocorticography and diffusion tensor imaging, the proposed studies will provide insight into the electrophysiologic and anatomic basis of BOLD fMRI signals and thereby augment the design and interpretation of future basic science and clinical fMRI-based brain mapping studies.